NM_000129.4:c.1766T>A

Variant names:

• chr6-6167600-A-T
• rs5983
• NM_000129.4:c.1766T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000129.4(F13A1):​c.1766T>A​(p.Leu589Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,613,720 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L589M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (25 hom.)
• Consequence: F13A1 NM_000129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.179
• Publications: 14 publications found

Genes affected

F13A1 (HGNC:3531): (coagulation factor XIII A chain) This gene encodes the coagulation factor XIII A subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as plasma carrier molecules. Platelet factor XIII is comprised only of 2 A subunits, which are identical to those of plasma origin. Upon cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. It also crosslinks alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone. These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion. [provided by RefSeq, Jul 2008]

F13A1 Gene-Disease associations (from GenCC):

• factor XIII, A subunit, deficiency of

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• congenital factor XIII deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014963478).
• BP6: Variant 6-6167600-A-T is Benign according to our data. Variant chr6-6167600-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 786407.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00431 (656/152226) while in subpopulation NFE AF = 0.00622 (423/68016). AF 95% confidence interval is 0.00573. There are 9 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	NM_000129.4	MANE Select	c.1766T>A	p.Leu589Gln	missense	Exon 13 of 15	NP_000120.2	P00488

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F13A1	ENST00000264870.8	TSL:1 MANE Select	c.1766T>A	p.Leu589Gln	missense	Exon 13 of 15	ENSP00000264870.3	P00488
	F13A1	ENST00000950947.1		c.1766T>A	p.Leu589Gln	missense	Exon 12 of 14	ENSP00000621006.1
	F13A1	ENST00000878383.1		c.1577T>A	p.Leu526Gln	missense	Exon 12 of 14	ENSP00000548442.1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152108 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00379 AC: 951 AN: 251142 AF XY: 0.00374

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00521 AC: 7609 AN: 1461494 Hom.: 25 Cov.: 32 AF XY: 0.00512 AC XY: 3725 AN XY: 727056

African (AFR) AF: 0.000837 AC: 28 AN: 33466

American (AMR) AF: 0.00188 AC: 84 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 276 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00173 AC: 149 AN: 86222

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53418

Middle Eastern (MID) AF: 0.00109 AC: 6 AN: 5506

European-Non Finnish (NFE) AF: 0.00603 AC: 6704 AN: 1111980

Other (OTH) AF: 0.00451 AC: 272 AN: 60362

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152226 Hom.: 9 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74432

African (AFR) AF: 0.00145 AC: 60 AN: 41520

American (AMR) AF: 0.00549 AC: 84 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00592 Hom.: 2

Bravo AF: 0.00365

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00575

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Factor XIII, A subunit, deficiency of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.53
DANN	Benign	0.59
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.080	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.18
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.062
Sift	Benign	0.63	T
Sift4G	Benign	0.62	T
Vest4		0.26
MVP		0.33
MPC		0.24
ClinPred		0.00055	T
GERP RS		-2.0
gMVP		0.72
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5983; hg19: chr6-6167833;